The hypothesis upon which this Program Project Grant is based is that hemodynamic loading of the heart is the primary regulator of its structure and function. While the predictions of this hypothesis are equally applicable to cardiac physiology and pathophysiology, the question which we have chosen as the subject of these studies is that of how increased load interacts directly with the heart to explain the causes and consequences of cardiac hypertrophy. In this context, the six individual projects form a closely interrelated set of studies. In the first Project, Dr. McDermott will turn from the question of how translational mechanisms control general protein synthesis during cardiac hypertrophy to the question of how these mechanisms regulate the expression of specific proteins that are required for this growth process. In the second Project, Dr. Spinale will focus on the growth and remodeling that occurs after myocardial infarction in terms of how specific matrix metalloproteinases affect this process. In the third Project, Dr. Menick will extend his work on the Na+-Ca2+ exchanger to the study of a regulatory mechanism wherein alterations of exchanger activity may directly activate signal transduction pathways, resulting in changes in exchanger gene expression. In the fourth Project, Dr. Cooper will extend his work showing augmented microtubules in hypertrophied myocardium to a direct test of whether a dense, stable microtubule network is the cause of the associated contractile dysfunction and then seek the basis for this hypertophic cytoskeletal change in terms of increased phosphorylation-dependent affinity of upregulated MAP4 for the microtubules. In the fifth Project, Dr. Kuppuswamy will ask how cardiac load is translated by integrins into modulation of intracellular signals for hypertrophy by defining the mechanisms of focal adhesion complex assembly during integrin activation and then defining the role of the focal adhesion complex in hypertrophy. In the sixth Project, Dr. Zile will extend our previous focus on hypertrophy-related systolic dysfunction to a consideration of cellular mechanisms responsible for hypertrophy-related diastolic dysfunction, especially in terms of cardiocyte viscoelastic properties that may be altered in the hypertrophied and aging heart. Thus, the first and fifth projects are concerned with causes of load-induced cardiac hypertrophy in the adult, with the first focused on induction of increased protein synthesis, and the fifth focused on signals for that induction. The other four projects are concerned with consequences of load-induced cardiac growth in the adult, being focused on mechanisms by which changes in structural and regulatory factors, both intracellular or extracellular, alter contractile function and its regulation in hypertrophy.